Project Summary/Abstract Parkinson?s Disease (PD) is a debilitating neurodegenerative condition that results in profound motor deficits. The motor symptoms in PD patients are first treated with the drug levodopa, but following the development of levodopa-induced motor abnormalities patients are often implanted with a deep brain stimulator in the subthalamic nucleus (STN DBS). While STN DBS is effective, optimization of DBS has been limited by a lack of understanding concerning its mechanism. Patients are often stimulated chronically at high frequency (HFS), but it has been difficult to test the necessity of HFS and the efficacy of other stimulation paradigms in a rigorous fashion in humans. One prevailing theory is that STN DBS acts primarily by inhibiting the STN; however evidence for this theory has been hampered by a lack of models allowing for artifact-free, cell-specific interrogation of the circuit. With this in mind, we developed a novel technique to perform effective STN DBS in a parkinsonian mouse. Using this mouse model along with fiber photometry, we plan to characterize the parameter space for therapeutic DBS and to investigate the hypothesis that STN DBS inhibits the STN and downstream nuclei. These experiments will be the first to rigorously explore the parameter space for STN DBS, as well as the first to investigate the effect of STN DBS on relevant regions of the brain in an artifact-free, cell- specific manner. Additionally, they may provide insight into how to improve STN DBS therapy for future patients.